The objective of this project is to identify, characterize and manipulate the HLA-encoded parameters associated with susceptibility to rheumatoid arthritis (RA). Our focus is on the "shared epitope" --a specific cluster of MHC class II residues with immunologic and genetic properties implicated in RA. We propose to (1) modulate recognition of RA-associated HLA molecules through the design of specific peptide mimetics which recapitulate antibody and T cell receptor recognition directed to the shared epitope structure; and (2) analyze recognition of the shared epitope both in the context of.trimolecular interactions involving direct T cell receptor contact and also as a peptide, processed and re-presented as a traditional antigenic determinant. These aims are based on the hypothesis that the genetic association of RA with the shared epitope sequence reflects an important immunologic event in pathogenesis which is an appropriate target and opportunity for novel therapeutic directions. A combination of experimental and computational approaches will be used to precisely identify the key structure/function components involved in recognition of the RA-associated shared epitope.